Roundtable Discussion: Moon Discusses Best Path for Maintenance Care in Advanced Bladder Cancer

Helen Moon, MD (Moderator)

Principal Investigator, Cancer Clinical Trials Access Program

Southern California PermanenteMedical Group

Riverside, CA

CASE SUMMARY

A 66-year-old woman was referred by the urology department after evaluation for gross hematuria with an estimated glomerular filtration rate of 50 mL/min and a cystoscopy showed a nodular 7-cm mass along the posterior bladder wall. A CT scan of the chest, abdomen, and pelvis showed evidence of pelvic lymphadenopathy and lung metastases. The patient has a 30-year smoking history and a medical history that includes chronic obstructive pulmonary disease, mild hypertension, and coronary artery disease with no prior myocardial infarction.

She had a tumor proportion score of 65% PD-L1 and received carboplatin plus gemcitabine for 4 cycles. This treatment was discontinued because of toxicity. She had stable disease on imaging, but she was started on avelumab 800 mg given intravenously every 2 weeks as maintenance therapy. There were no new lesions on repeat imaging, and she has an ECOG performance status of 0. Liver function tests, creatinine clearance level, and other lab results were within normal limits, but she continues to smoke at least 1 pack per day. There are no infusion reactions.

DISCUSSION QUESTIONS

• Which end points are meaningful to you in the switch maintenance setting?
• For a patient like this, would you ever consider a single-agent immune checkpoint inhibitor over gemcitabine/carboplatin then avelumab? If yes, when?

MOON: At the point where you’re selecting the first-line therapy, why did you decide [on] chemotherapy? Would you ever do just first-line immunotherapy, in which case they would never get switch maintenance and so on?

DEKKER: I can see the situation evolving in different ways. One, the patient says, “Okay, I want a break; I don’t want any treatment because I am tired. I stopped because of toxicities.” I’ll go on to a 3-month break and then we’ll talk, but we discuss the decision; however, it’s her life to make these decisions with. Now, in the second-line therapy, because she is PD-L1 positive, I would be comfortable [using] single-agent immunotherapy in the second line, but one of the reasons that I started using maintenance [therapy] relatively quickly is because it is generally, except for financial toxicity, well tolerated.

MOON: OK, so what I’m hearing is ease of use, right?

JANG: Well the reason why you want to use it is you’ve got a 9-month overall survival [OS] benefit. I think the important thing is a couple of things that you are sure of. An American Society of Clinical Oncology [ASCO] Genitourinary Cancers [Symposium] 2022…update showed that in the JAVELIN Bladder 100 [NCT02603432] subgroup analysis, [for] patients who had visceral disease this regimen was less effective.¹

Contrary to what Dr Dekker said, if this patient progresses and has lung or liver metastases, you should not use single-agent immunotherapy. Absolutely not. Because if a patient has liver or lung metastases, single-agent immunotherapy in the second line is not very effective, so you must go with more targeted therapy or EV [enfortumab vedotin (Padcev) or sacituzumab govitecan (Trodelvy)] or treatments like that. The PD-L1 expression has no value in the frontline space because [responses can be] unpredictable, so I don’t think you need to even check PD-L1 expression in the front line.

SARKISSIAN: I agree, because bladder cancer is one of the few scenarios [from which] the FDA pulled a couple of immunotherapy drugs.

MOON: Durvalumab [Imfinzi] and atezolizumab [Tecentriq] were pulled off.

SARKISSIAN: For whatever reason, it tends to work in certain scenarios, but there were data on the combination of enfortumab and pembrolizumab [Keytruda]. I don’t think immunotherapy was totally off the table. I think ipilimumab [Yervoy] plus nivolumab [Opdivo] has panned out, so immunotherapy has a place, but it’s going to need to act in synergy with something else, whether it’s going to be these antibody-drug conjugates like enfortumab or sacituzumab with chemotherapy priming at the same time [or something else]. I don’t think nivolumab plus chemotherapy has panned out well, but I still think it has a place synergistically.

MOON: I think what you’re alluding to was back in the late [2010s]; at one point, 5 drugs were approved in some variation in the space, so [in other words] all of them: atezolizumab, avelumab [Bavencio], nivolumab, pembrolizumab, and durvalumab. Since then, as they were asked to do the confirmation studies, 2 companies [have] pulled their requests for approval with a statement…[for] durvalumab and atezolizumab, and they lost their designation for that. So in the market there are 3 remaining therapies: pembrolizumab, nivolumab, and now avelumab primarily in switch maintenance [for this patient population].

I think what I’m hearing from Dr Jang is that the most compelling part of the JAVELIN Bladder 100 [data] is that OS, the good old-fashioned [indicator], is significantly better, and we are going to have to give patients that opportunity. He also talked a little bit about patients with visceral disease not doing as well. When this trial result was discussed at the ASCO [meeting], one of the discussion questions was [whether] there is room for a gap. Meaning, can you do the chemotherapy.

If you have that patient that you don’t think is going to disappear on you, can you keep watching them so that you catch them at the first sign of relapse and start immunotherapy? In that case, one could have any of the 3 options, and that could effectively be 9 months or 1 year of being off drugs vs going straight to avelumab. Is that something feasible? That trial will probably never be done, but that, at the end, is the question of switch maintenance vs true second-line therapy in a monitored fashion. I don’t think we have an answer to that now.

MOON: I think the pro, as Dr Dekker said, is [that] it is a relatively easy drug to give, while the cons include financial toxicity.

DISCUSSION QUESTION

• What do you view as the pros and cons of using avelumab maintenance therapy?

HAMPSHIRE: In the patients who were studied in the JAVELIN Bladder 100 study, I think it’s a relatively easy decision in terms of if they have either stable disease or response to a platinum-based up-front therapy [From the Data¹]. Switching them, whether it’s after 4 or 6 cycles based upon toxicity, to a maintenance immunotherapy, whether they’re PD-L1 positive or negative, is pretty straightforward. I would not wait to start them on that simply because a response to avelumab with progressive disease after frontline therapy, even if it happens, would take longer to get under control. I think you’ve got only a finite time to get progressive bladder cancer under control.

As we were talking about it, I was thinking about another patient of mine currently who is not cisplatin [Platinol] eligible and is on gemcitabine plus paclitaxel [Taxol] and is doing relatively well and appears to have a response. And now we’re getting into the fourth cycle of treatment and a little bit more toxicity.

Now I’m thinking about switch maintenance therapy for them. Is it the platinum that’s important or is it the response that’s important? I personally am planning on switching him, if I can get it covered, to avelumab as a maintenance therapy. I think that it’s more of a response to the up-front therapy than it is the platinum eligibility that would lead to the benefit, but I realize that that’s a lot of assumptions.

MOON: Yes, that’s a fair point. I honestly would do the same thing because I also do think, are we just picking out the excellent responders or is it the platinum or is that just an easy surrogate for functionality? Would anyone else give switch maintenance for a non–platinum-based regimen?

YEH: I would give [switch maintenance] in a patient that has a good response to chemotherapy. I think it’s probably worthwhile using a switch maintenance right away. I think there’s something about prior chemotherapy that activates the immune cells to make the immune system more potent.

There are multiple trials using chemoimmunotherapy that show a negative trial, is that correct? It’s only this trial using chemotherapy first, followed by maintenance, where there’s an OS benefit. There probably is something about the chemotherapy that’s activating something in the cancer cell that makes the immune system more active.

MOON: Yes, bladder cancer up front is littered with negative combination-chemoimmunotherapy trials, which to this day I still don’t 100% understand.

YEH: Yes, with platinum per se. I think if you use chemotherapy followed by maintenance therapy, there probably is some synergy between those 2.

DISCUSSION QUESTIONS

• How do you/will you counsel patients regarding use of maintenance therapy with avelumab?
• What are the key points of education during shared decision-making? What about during therapy?

MOON: Dr [Stephen], have you ever had a situation where you offer patients maintenance avelumab and they respond, “No, thank you”? Is it as generic as “I’m just sick of coming and I want time off,” or is there something that they are unsure about or do most people just accept [it]?

STEPHEN: I haven’t been able to offer avelumab, but… this is a common discussion—the maintenance immunotherapy after the initial treatment. Most people are agreeable. If there are any kind of survival data and you talk about how ubiquitous immunotherapy is now, a lot of people are aware of it. They want to try it. If I believe in the approach, I sell it as maintenance and that you’ll be able to carry on your usual lifestyle. If you’re not a patient who has a lot of toxicity, it’s possible to carry on most of your day-to-day life, so then most people want to try it.

MOON: I think that’s fair.

CHO: Yes, so in a way [the avelumab trial] subselected a good group of patients. Is that why the avelumab maintenance is positive, rather than the negative chemoimmunotherapy? Would that be a possibility?

MOON: Yes, that’s one of the things you think about.… Dr Jang, if I remember correctly, you may have mentioned dose-dense MVAC [methotrexate (Trexall, Otrexup), vinblastine (Velban), doxorubicin (Adriamycin), and cisplatin], where you’re seeing a response rate in the 70% range. Gemcitabine plus cisplatin is about 50% or in that neighborhood. So if you’re thinking that what comes into the treatment funnel is 100 patients with metastatic bladder cancer, half of them would not ever go on to maintenance because they would have progressed. In some ways, have you selected out all your bad players and cherry-picked the good players and kept going?

These are the questions that I guess go into how standard of care or rock solid you think avelumab maintenance is. There are [strong] proponents of it. In some ways, 80% of people just think that that’s the standard. It’s a clean standard. You give platinum and you move on or in the case of chemotherapy, you get a nice, deep response.

DISCUSSION QUESTION

• How will use of switch maintenance therapy change the overall treatment paradigm in advanced urothelial carcinoma?

DEKKER: I would say that currently, things are changing so rapidly, so you could say it’s standard. It probably will be standard for 1 to 3 patients. For the fourth patient 3 months later, it probably will be a different standard or a different situation, or this slightly different trial either published or leaked [data] or something else.

Trials with all kinds of other combinations are used or considered, so I generally don’t like to say anything is standard because it changes so quickly. Today it looks great. Tomorrow you’ve got a slightly different piece of information, or you talk to an old friend who tells you that X, Y, Z, or whatever data, were not used in the analysis. If they were used, the results would be slightly different.

MOON: I agree, and this dovetails nicely with the question. I’ve got to tell you, when these data came through it was very vexing for a lot of clinical trials that were written post platinum, and they have some immunotherapy in there.

_REFERENCE

1. _{Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022;40(suppl 6):487. doi:10.1200/ JCO.2022.40.6_suppl.487}